Neuropathic pain is currently affecting 7–10% of the world population. Therapeutic strategies include antidepressants, antiepileptics, local anesthetics and opioids. These treatments are effective in less than 50% of patients, and they are characterized by many side effects, that limit their long-term use. In this work, we evaluated the possible anti-hyperalgesic effect of non-psychotropic Cannabis sativa L. oil extracts in an animal model of peripheral neuropathic pain. To identify the possible synergy and interaction between cannabinoids and terpenes, we compared an extract (K1) devoid of terpenes and with high a concentration of cannabidiol (CBD) with one (K2) containing a high level of both classes of compounds. The detailed chemical characterization the oil extracts was carried out by ultra-high-performance liquid chromatography (UHPLC), coupled with high-resolution mass spectrometry (HRMS), using a targeted metabolomic approach. Among all the identified cannabinoids, the most representative ones were further quantified by HPLC-UV. Volatile compounds in the oils were fully analyzed by GC-MS. The activity of the oil extracts after oral administration was assessed by measuring mechanical and thermal allodynia using the spared nerve injury (SNI) model in mice. The mechanism of action of K2 was investigated using spinal cords samples in a cell-based in vitro model of neuroinflammation. Oral administration of K2 at 25 mg kg−1 ameliorated mechanical and thermal allodynia in SNI mice, with a rapid and a long-lasting effect, without inducing an alteration of locomotor activity, with an efficacy higher than K1. K2 reduced p-ERK, p-p38 and p-JNK1 protein levels compared to the untreated mice. Moreover, the extract downregulated protein expression of neuroinflammatory factors (HDAC-1, p-65, NOS2). To deeper investigate the possible synergism of CBD and β-caryophyllene (CAR), which are the two main compounds among cannabinoids and terpenes, respectively, an in silico structure-based approach was performed on CB2 receptors. CBD was predicted to bind close to the binding site entrance, while CAR was docked deeper into the binding site. Together, CBD and CAR were able to resemble the experimental binding mode of the reference ligand and the interactions with the binding site residues better than CBD and CAR alone, which could explain the higher activity of K2 compared to K1. In vitro binding and functional assays are currently ongoing to validate the in silico results.

Disclosing the role of cannabinoids and terpenes in the fight against neuropathic pain

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